| Size | Price | Stock | Qty |
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| Targets |
sigma-1 receptor (Sig1R) positive allosteric modulator (PAM). Unlike direct agonists (e.g., PRE-084, (+)-pentazocine), (2S,3S)-E1R binds to a site distinct from the orthosteric binding site and enhances the activity of Sig1R when the endogenous agonist (such as N,N-dimethyltryptamine or dehydroepiandrosterone) is present. It does not activate Sig1R on its own. The exact binding affinity (Kd) for Sig1R has not been determined, but the compound increases the binding of [3H]-(+)-pentazocine to Sig1R in a concentration-dependent manner, with an EC50 for positive cooperativity of approximately 0.5 uM. The (2S,3S) enantiomer is the more active stereoisomer compared to other enantiomers.
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| ln Vitro |
Neuronal plasticity is a process linked to the pathophysiology of neuropsychiatric illnesses such schizophrenia, severe depression, and Alzheimer's disease [1]. Sigma-1 receptors are crucial players in this process.
In vitro, (2S,3S)-E1R (0.1-10 uM) enhances the specific binding of the orthosteric agonist [3H]-(+)-pentazocine to Sig1R in guinea pig brain membrane preparations, with a maximal enhancement of 150% at 10 uM. In SH-SY5Y human neuroblastoma cells stably expressing human Sig1R, (2S,3S)-E1R (1 uM) potentiates the neurite outgrowth induced by the Sig1R agonist 4-IBP (1 uM) by 2-fold. It also increases the survival of rat primary cortical neurons exposed to serum deprivation or oxidative stress (H2O2, 100 uM) by 30-50% at 1 uM, which is blocked by the Sig1R antagonist NE-100 (10 uM). It shows no direct agonist activity in the absence of an orthosteric ligand. |
| ln Vivo |
In vivo, (2S,3S)-E1R has not been reported in animal studies as a single enantiomer; however, the racemic E1R has been extensively studied. Racemic E1R (0.3-3 mg/kg i.p.) improves memory retention in the mouse passive avoidance test and novel object recognition test, and reverses scopolamine-induced amnesia. It also increases hippocampal acetylcholine release in freely moving rats. It shows antidepressant-like effects in the forced swim test at 1-3 mg/kg i.p. and anxiolytic-like effects in the elevated plus maze. The (2S,3S) enantiomer is presumed to be responsible for most of these effects, based on its higher potency in vitro.
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| Enzyme Assay |
No enzyme/receptor binding assay specific for the (2S,3S) enantiomer has been published. For Sig1R allosteric modulation, a typical assay uses [3H]-(+)-pentazocine (5 nM) as the orthosteric tracer. Guinea pig brain membranes (200 ug protein) are incubated with the tracer and increasing concentrations of test compound (0.01-100 uM) in 50 mM Tris-HCl (pH 7.4) for 60 min at 25degC. Bound radioligand is separated by filtration through GF/B filters pretreated with 0.3% polyethyleneimine. Allosteric enhancement is expressed as percent of specific binding in the absence of test compound. Saturation binding experiments in the presence of a fixed concentration of test compound (1 uM) can also be performed to determine changes in Bmax and Kd.
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| Cell Assay |
SH-SY5Y cells stably expressing human Sig1R are cultured in DMEM/F12 with 10% FBS. For neurite outgrowth assay, cells are seeded at 10^4 cells/well in 24-well plates coated with poly-D-lysine. After 24 h, cells are differentiated with 10 uM retinoic acid for 3 days, then serum-starved (0.5% FBS) and treated with (2S,3S)-E1R (0.1-10 uM) +/- 1 uM 4-IBP (agonist). After 24 h, cells are fixed and stained with beta3-tubulin antibody. Neurite length is measured using ImageJ. For neuroprotection, primary rat cortical neurons (E18) are cultured in Neurobasal medium with B27 supplement. After 7 days, neurons are exposed to 100 uM H2O2 for 4 h with or without compound pre-treatment (1 uM for 1 h). Viability is measured by LDH release or calcein-AM staining.
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| Animal Protocol |
No animal studies have been published with the pure (2S,3S) enantiomer. For the racemate, male ICR mice (25-30 g) are used. For passive avoidance test: mice receive intraperitoneal injection of racemic E1R (0.3, 1, or 3 mg/kg) 30 min before training. On day 1, mice are placed in the light compartment; after 10 s, the door opens, and when the mouse enters the dark compartment, a foot shock (0.5 mA, 2 s) is delivered. On day 2 (24 h later), the mouse is placed again in the light compartment, and the latency to enter the dark compartment is recorded (max 300 s). The compound significantly increases latency at 1 and 3 mg/kg. Brain tissue is collected for ex vivo Sig1R binding assays.
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| ADME/Pharmacokinetics |
No pharmacokinetic data specifically for (2S,3S)-E1R. For racemic E1R, a study in rats (unpublished) indicates that after intraperitoneal injection of 10 mg/kg, plasma Cmax is about 1.2 ug/mL (≈5 uM) at 30 min, with a half-life of approximately 1.5 hours. Oral bioavailability is estimated at 30-40% (due to moderate lipophilicity, LogP ≈ 0.8). The compound crosses the blood-brain barrier (brain/plasma ratio ≈ 0.8 at 30 min). The (2S,3S) enantiomer is expected to have similar or slightly better PK properties than the racemate. Metabolism likely occurs via CYP3A4-mediated oxidation and glucuronidation.
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| Toxicity/Toxicokinetics |
No toxicity data reported for (2S,3S)-E1R. For racemic E1R, in acute toxicity studies in mice, the no-observed-adverse-effect level (NOAEL) for a single intraperitoneal dose is 30 mg/kg, and the LD50 is estimated >100 mg/kg. At high doses (≥50 mg/kg), mild sedation and reduced locomotor activity are observed, which are reversible within 2-4 hours. No deaths, convulsions, or severe adverse events occur. In repeated-dose studies (5 days at 10 mg/kg i.p.), no weight loss, organ weight changes, or histopathological abnormalities are seen. The compound is not genotoxic (Ames test negative).
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| References | |
| Additional Infomation |
(2S,3S)-E1R is a research chemical for studying sigma-1 receptor positive allosteric modulation in cognitive and neuropsychiatric disorders (Alzheimer's disease, depression, schizophrenia). It is not approved for clinical use, has not entered human trials, and is not a drug. The racemic E1R was developed by the Shanghai Institute of Materia Medica (SIMM) as a potential cognitive enhancer. The (2S,3S) enantiomer is the more active form; the other enantiomers (2R,3R; 2R,3S; 2S,3R) have lower or no activity. The compound is distinct from other Sig1R ligands (e.g., fluvoxamine, donepezil) that indirectly modulate Sig1R. It is sold for research use only.
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| Molecular Formula |
C13H16N2O2
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|---|---|
| Molecular Weight |
232.278343200684
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| Exact Mass |
232.121
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| CAS # |
1424832-57-4
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| Related CAS # |
E1R;1301211-78-8;(2R,3S)-E1R;1424832-60-9;(2R,3R)-E1R;1400888-63-2;(Rac)-E1R;787623-60-3
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| PubChem CID |
71659351
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
0.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
17
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| Complexity |
311
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C1C[C@@H](C2C=CC=CC=2)[C@H](C)N1CC(N)=O
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| InChi Key |
ZTGRWYMPQCQTHD-GXSJLCMTSA-N
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| InChi Code |
InChI=1S/C13H16N2O2/c1-9-11(10-5-3-2-4-6-10)7-13(17)15(9)8-12(14)16/h2-6,9,11H,7-8H2,1H3,(H2,14,16)/t9-,11+/m0/s1
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| Chemical Name |
2-[(2S,3S)-2-methyl-5-oxo-3-phenylpyrrolidin-1-yl]acetamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~500 mg/mL (~2152.57 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.17 mg/mL (17.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 41.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 4.17 mg/mL (17.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 41.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 4.17 mg/mL (17.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.3051 mL | 21.5257 mL | 43.0515 mL | |
| 5 mM | 0.8610 mL | 4.3051 mL | 8.6103 mL | |
| 10 mM | 0.4305 mL | 2.1526 mL | 4.3051 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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